(a) Field of the Invention
The invention relates to novel mimetopes of anti-PSMA antibodies and their use for detecting, imaging, staging, treating and monitoring of prostate cancer, and/or metastasis thereof. Furthermore, the invention also relates to novel pharmaceutical compositions for the treatment of prostate cancer.
(b) Description of Prior Art
The prostate gland is affected by various significant pathological conditions as benign growth (BPH), infection (prostatitis), and neoplasia (prostate cancer).
Prostate cancer is the second most frequently diagnosed cancer in Canadian and American men, after non-melanoma skin cancer, which is rarely fatal. More importantly, after lung cancer, prostate cancer is the most common cause of cancer-related death. The risk of developing prostate cancer increases significantly with age, particularly for men over 50. For men under 50 years of age the disease is uncommon and death from it is rare.
Prostate cancer accounts for an estimated 28% of newly diagnosed cancer in Canadian men and more than 12% of cancer-related deaths. The current lifetime risk of a Canadian man being diagnosed with prostate cancer is about 1 in 8. In the United States, prostate cancer accounts for approximately 32% of male cancer diagnoses and 14% of cancer deaths. Studies in the United States suggest that the incidence rate may be approaching 1 in 6 men.
Because the incidence of prostate cancer increases with age, it is clear that the burden of this illness will increase dramatically in the coming decades. The aging of the population, particularly the baby boomers, will have important long-term implications for the number of new cases diagnosed. Demographic trends in the next two decades will increase the population at risk for prostate cancer. Statistics Canada projections indicate that the population of men over age 50 will increase from 3.9 million in 1999 to 5.6 million in 2011 (44% increase) and 6.3 million in 2016 (62% increase). The United States Census Bureau projections indicate that the population of men over age 50 will increase from 33.8 million in 1999 to 45.8 million in 2011 (36% increase) and 50.7 million in 2016 (50% increase).
As a consequence of the expected increases in the number of cases of prostate cancer in the coming years due to rising incidence rates and the aging North American population, more resources will likely be allocated to screening men over 50 for this condition, therefore yielding an increase in the number of cases of identified prostate cancer.
Prostate cancer often exhibits a long latency period. However, it is believed that prostate cancer often remains undetected. Also, because it possesses a high metastatic potential to bone and the lymph nodes, with <10% of individuals diagnosed with prostate cancer also demonstrated, by radionuclide scans, to have bone metastasis, prompt detection and treatment is needed to limit mortality caused by this disease. A recent review of treatment of prostate cancer is by Pirtskhalaishvilig et al. (2001, Cancer Practice 9(6):295).
Increased detection of prostate cancer is due in part to increased awareness and the widespread use of clinical markers such as prostate specific antigen (PSA). Prostate specific antigen is a protein that is produced in very high concentrations in prostate cancer cells. Cancer development results in an altered and subsequent loss of normal gland architecture. This in turn leads to an inability to remove secretions and thus the secretions reach the serum. Serum PSA measurement is one method for screening for prostate cancer.
The current diagnostic and treatment paradigm for prostate cancer is reflected in Clinical Practice Guidelines that are widely available to practicing physicians. The guidelines presented below outline the common approach to the detection and management of prostate cancer.                The Prostate Specific Antigen test is a blood test used to detect prostate cancer in the earliest stages and should be offered annually to men 50 and older with a life expectancy of 10 years or more, and to younger men at high risk for prostate cancer.        The Digital Rectal Exam (DRE) is a test that helps to identify cancer of the prostate, and should be performed on men who are 50 and older and to younger men at high risk for prostate cancer.        A biopsy is recommended for all men who have an abnormal PSA or DRE.        The options for primary management of prostate cancer are surgery, radiation therapy or close observation. Treatment decisions are based on the aggressiveness of the cancer, the stage of the cancer and the life expectancy of the individual.        Advanced prostate cancer is best managed with hormone therapy.        Radiation therapy can include external and implanted seeds, a procedure known as brachytherapy.        
The PSA test, which facilitates early detection of prostate cancer, has been available in Canada since 1986, although its use did not become widespread until the early 1990's. In 1994 the U.S. Food and Drug Administration (FDA) approved the use of the PSA test in conjunction with DRE as an aid in detecting prostate cancer. The free PSA test (fPSA), a more sensitive test for prostate cancer risk than the standard PSA test, received FDA approval in 1998.
Because of the limitations of the PSA test (lack of specificity for prostate cancer and a significant number of “false positive” and “false negative” test results) it remains an investigational tool as opposed to an absolute diagnostic test.
Prostate biopsies are performed to confirm the presence of cancer cells following suspicion raised by the DRE or a positive PSA test. The most commonly reported complications of biopsy consist of traces of blood in the urine, semen or feces. Prostatic biopsy represents the cornerstone of prostate cancer diagnosis.
For prostate cancers in general, biopsies miss cancers at a rate estimated as high as 50 percent. Furthermore, even if a cancer is detected, the location and staging of cancerous cells are not adequately identified.
Thus, there is a need for an improved method for diagnosis and/or detection of cancerous prostate cells.
An important prognostic factor is prostate cancer stage. Cancer staging is performed to determine the extent and spread of cancer in the prostate. Prostate cancer metastasizes by local spread to the pelvic lymph nodes, seminal vesicles, urinary bladder, or pelvic side walls and to distant sites such as bone, lung, liver, or adrenals.
The cancer foci have different malignant potentials and do not pose equal risks for the individual. Heterogeneity confounds the interpretation of positive prostate biopsies since it is not possible to be certain that the most clinically relevant foci of cancer have been detected.
Approximately only 30% of early stage disease will progress to clinically relevant disease within the lifetime of the individual. It is therefore critical to be able to identify those individuals at risk of progression who would benefit from aggressive therapy while sparing low-risk individuals the morbidity resulting from aggressive treatment of indolent disease. Neither rising PSA nor the presence of cancer cells on biopsy may indicate definitively the presence of lethal disease.
A new prostate imaging technology that provides for accurate visualization of extraprostatic growth indicative of metastasis would provide physicians with a tool to determine the progression of the cancer and would be extremely valuable in directing treatment options. Spectroscopy significantly improves the diagnosis of extracapsular extension by MRI. However, studies demonstrate that there is high variability in how clinicians interpret the significance of extracapsular extension. Both CT and MRI can be helpful in staging prostate cancer, because they can indicate periprostatic cancer spread, lymph node abnormality and bone involvement, but their sensitivity for revealing cancer extension has limitations.
Thus, there is a need for a non-invasive test that is able to identify lymph node metastases in individuals at risk for extraprostatic disease following the detection of elevated PSA and/or abnormal DRE and a positive biopsy. This will allow clinicians to reliably differentiate individuals with organ-confined disease from those with metastatic spread to lymph nodes. This will provide the opportunity for the individual and physician to make an informed decision on how to treat the disease and will significantly improve individual health outcome.
Furthermore, a new technology that is able to localize cancerous prostate cells that remain following radical prostatectomy would assist physicians in removing all of the cancerous cells from an individual's body with focused treatment such as radiation therapy. A labeled technology that selectively binds prostate cancer cells will allow clinicians to localize any remaining cancer cells following surgery. An additional new technology would provide direct delivery of therapeutic agents, perhaps preventing the need for surgery.
Thus, there is a need for an improved method to detect and/or diagnose lymph node metastases in individuals at risk for extraprostatic disease following the detection of elevated PSA and/or abnormal DRE and a positive biopsy.
A substantial amount of work has been put into identifying enzyme or antigen markers, which could be used as sites for detection and/or diagnosis for various types of cancers. These markers could also be used to target cancer cells for treatment with therapeutic and/or cancer cell killing agents. The ideal cancer marker would exhibit, among other characteristics, tissue or cell-type specificity.
A 750 amino acid protein (FIG. 2; SEQ ID NO:2), prostate-specific membrane antigen (PSMA), localized to the prostatic membrane has been identified. The complete coding sequence of the gene (FIG. 1; nucleotides 262 to 2514 of GenBank™ accession number NM—004476) is presented as SEQ ID NO:1. PSMA is an integral Type II membrane glycoprotein with a short intracellular tail and a long extracellular domain. This antigen was identified as the result of generating monoclonal antibodies to a prostatic cancer cell, LNCaP (Horoszewicz et al. (1983) Cancer Res. 43:1809-1818). Israeli et al. (Israeli et al. (1993) Cancer Res. 53:227-230) describes the cloning and sequencing of PSMA and reports that PSMA is predominantly expressed in prostate derived cells and shows increased expression levels in metastatic sites and in hormone-refractory states. Other studies have indicated that PSMA is more strongly expressed in prostate cancer cells relative to cells from the normal prostate or from a prostate with benign hyperplasia. Current methods of targeting prostate specific membrane antigen use antibodies with binding specificity to PSMA. One of the first antibodies described with binding specificity to PSMA was 7E11 (Horoszewicz et al. (1987) Anticancer Res. 7:927-936 and U.S. Pat. No. 5,162,504). Indium-labeled 7E11 localizes to both prostate and sites of metastasis, and is more sensitive for detecting cancer sites than either CT or MR imaging, or bone scan (Bander (1994) Sem. In Oncology 21:607-612).
One of the major disadvantages of the 7E11 antibody is that it is specific to the portion of the PSMA molecule which is present on the inside of the cell (intracellular). Antibody molecules do not normally cross the cell membrane, unless they bind to an extracellular antigen, which subsequently becomes internalized. As such, 7E11 cannot be used to target a living prostate cell, cancerous or otherwise. The use of 7E11 for detection or imaging is therefore limited to pockets of dead cells within cancers or tissues with large amounts of dead cells, which cells render available their intracellular portion of PSMA for binding with this antibody.
U.S. Pat. No. 6,107,090, in the name of Neil Bander, and U.S. Pat. No. 6,150,508, in the name of Gerald Murphy et al. describe numerous monoclonal antibodies which recognize the extracellular domain of PSMA, thereby overcoming one of the major drawbacks of the 7E11 antibody. These antibodies, being able to bind to the extracellular domain of PSMA are capable of binding to living prostate cells, thereby allowing a more effective method of diagnosis than 7E11.
As described above, antibodies to PSMA are already in use for diagnostic purposes. For example, PSMA is the antigen recognized by the targeting monoclonal antibody used in ProstaScint™, Cytogen's imaging agent for prostate cancer. However, despite the benefits of antibodies, they possess several drawbacks which make them less than ideal for use in methods of detection, diagnosis and/or treatment of prostate cancers. Specifically, antibodies are high molecular weight proteins in the 150 kDa range and therefore display poor tissue penetrability. Furthermore, mouse monoclonal antibodies act as antigenic targets for the immune system, which results in biological instability in vivo.
It would be highly desirable to be provided with a small molecule, such as a mimetope to overcome the drawbacks of antibodies (Ab) as detailed above, but that retain similar high specificity and affinity of monoclonal antibodies (mAb). A mimetope is a synthetic binding agent and/or derivatives thereof having binding characteristics which imitate or mimic the binding characteristics of a molecule, including a protein and an antibody,
The use of mimetopes presents advantages over the use of antibodies for detection, diagnosis and/or treatment of prostate cancer because of their accessibility to cancer sites. Mimetopes eliminate the problems inherent in using, for example, mouse monoclonal antibodies in humans. Mouse monoclonal antibodies induce antibodies that will clear xenogenic antibodies used for detection, diagnosis and/or treatment of prostate cancer.
It would be highly desirable to be provided with an improved method for diagnosis and/or detection of cancerous prostate cells.
It would be highly desirable to be provided with a new prostate imaging technology offering accurate visualization of extraprostatic growth indicative of metastasis which would provide physicians with a tool to determine the progression of the cancer and be extremely valuable in directing treatment options.
It would be highly desirable to be provided with a non-invasive test that is able to identify lymph node metastases in individuals at risk for extraprostatic disease following the detection of elevated PSA and/or abnormal DRE and a positive biopsy.
It would be highly desirable to be provided with an imaging technology that decreases morbidity by identifying individuals in which surgery is not indicated.
It would be highly desirable to be provided with a new technology that is able to localize cancerous prostate cells that remain following radical prostatectomy which would assist physicians in removing all of the cancerous cells from an individual's body. In addition, it would be highly desirable to be provided with a new technology which would provide direct delivery of therapeutic agents, perhaps preventing the need for surgery.
It would be highly desirable to be provided with an improved method to detect and/or diagnose lymph node metastases in individuals at risk for extraprostatic disease following the detection of elevated PSA.
It would be highly desirable to be provided with an improved molecule over antibodies which would possess characteristics able to overcome the drawbacks and disadvantages present with antibodies.
It would be highly desirable to be provided with a new prostate imaging technology that provides for accurate visualization of extraprostatic growth indicative of metastasis which would provide physicians with a tool to determine the progression of the cancer and be extremely valuable in directing treatment options.
It would be highly desirable to be provided with novel mimetopes of anti-PSMA monoclonal antibodies and their use for detecting, imaging, staging, treating and monitoring of prostate cancer, and/or metastasis thereof. It would also be highly desirable to be provided with novel pharmaceutical compositions for the treatment of prostate cancer.